Treatment Strategies for a Complex Neuromuscular Disease: The Pompe StoryNeuromuscular Disease: The Pompe Story

Barry J. Byrne, MD, PhD

Pediatrics and Powell Gene Therapy CenterUniversity of Florida College of MedicineUniversity of Florida, College of Medicine

2

4

Initial Presentation of Pompe Disease:Fatal Cardiomyopathy in Infancyy p y y

Background: Spectrum of DiseaseBackground: Spectrum of Disease

• Mutations in GAA gene with lysosomal accumulation of glycogenlysosomal accumulation of glycogen– Autosomal recessive– 1:40,000

• Heart disease: glycogen accumulation leading to increased cardiac mass and heart failure Respiratory

Speech &Hearing

• Muscloskeletal: severe weakness with early loss of motor milestones

• Respiratory disease: progressive F di /GI

Cardiac

p y p gloss of independent ventilation Feeding/GI

Musculoskeletal

Pompe Disease SpectrumPompe Disease Spectrump pp p

Age at onsetInfancy AdulthoodAge at onsetInfancy

onof

Pro

gres

sio

Cardiomyopathy

Rat

e o

Myopathy

100%

0%

Acid Alpha-Glucosidase Activity 40%

0%

InfantileInfantile--Onset Pompe Natural History Study: Onset Pompe Natural History Study: KaplanKaplan--Meier Plot of Time to Death*Meier Plot of Time to Death*pp

0 9

1.0

Median age at death: 8 7 months

0.7

0.8

0.9

nts

Aliv

e

Median age at death: 8.7 months

Survival at 12 mos.: 25.7%Survival at 18 mos : 14 3%

0.5

0.6

on o

f Pat

ien Survival at 18 mos.: 14.3%Survival at 24 mos.: 9.0%Survival at 36 mos.: 7.1%

0.2

0.3

0.4

Pro

porti

o

0.0

0.1

0.2

Age (months)0 6 12 18 24 30 36 42 48 54 60

*Based on n=163 with available data Kishnani et al., 2005

Pathophysiology of Pompe Disease

- Weakness syndromeCongenital defect affecting both - Congenital defect affecting both

cardiac structure and function

GlycogenGlycogeny gy g

Defect in glycogendegradation due todegradation due to

GAA deficiency

Neuromuscular disease progression from early affected muscle to permanent damage

U t t d Di P i

affected muscle to permanent damage

Untreated Disease Progression

Early disease ? Irreversiblemuscle damage

Reversiblemuscle damage

Damagedmusclemuscle damage muscle

Healthy lysosome

Lysosome (w/ glycogen accumulation)

Healthy muscle fibre

Damaged muscle fibre

Released glycogen/enzymes

Fat deposits

TREATMENT BASICS

Mouse Model of Pompe Disease

P ti t d t l d t ti l t l iPatient data leads to an essential tool in preclinical evaluation of therapeutic strategies

GAA-/- Mouse Model: Essential tooli l ti f th ti t t iin evaluation of therapeutic strategies

Raben et al., 1998

Cardiac Pathology – Loss of myofibrils with gy yglycogen accumulation

GAA-/-129/B6 G129/B6

Pompe Disease

Investigational Treatments and Investigational Treatments and Research Initiatives

• Enzyme replacement therapy– Supply enzyme by IV infusion– Clinical studies completed: 1702, 1602, LOTS– BMN-701 to begun January 2011

• Gene therapy– Supply the patient with functional gene for GAA

IND i d A t 2010 E lli– IND issued August 2010, Enrolling

• Pharmacological Chaperonef– Inhibition of enzyme activity rescues protein

misfolding for missense mutations.Hirschhorn R, et al. In: The Metabolic and Molecular Bases of Inherited Disease. 2000:3389-3420.Amalfitano A, et al. Genetics Med. 2001;3:132-138.

Development Development HistoryHistorypp yy2003: Infant Natural

History Studies completed

2005: Successful Infant Studies & LOPOS

Completed

2006: Myozyme® Approved by EMEA and FDA

2007: Importance of MutationStatus Recognized

2007: Successful LOTS study CompletedLOTS study Completed

2007: MTAP/ATAP Initiated in USas Bridge to FDA Approval of

Scale-up

2004: Launched the Pompe Registry & Initiated Expanded

A P 2005: DiagnosticAvailability of Blood Testing (Chamoles)

2007: Newborn Screening

Pilot Successful in Taiwan

Access Program

Development HistoryDevelopment Historyp yp y

Early 2010: LOTS Published in NEJM and Prescribing Information

Updated in Europe2009 : Immune Tolerance

Studies Initiated for CRIM NEG infants and those with high titers

August 2010: AAV Gene Therapy Study

March 2009: EMEA Approval of the L S l P i G l B l i

May, 2010: FDA approval of Lumizyme®

2007: High Dose/Dose Frequency Study completed

Large Scale Process in Geel, Belgiumq y y p

Enzyme Replacement (ERT) Studies:Enzyme Replacement (ERT) Studies:AGLUAGLU 16021602 and AGLUand AGLU 17021702AGLU AGLU 1602 1602 and AGLU and AGLU 17021702

GoalsGoals• To expand ERT experience in infantile onset Pompe patients treated from

6 36 th f (1702) <6 th (1602)6-36 months of age (1702) or <6 months (1602).

Inclusion CriteriaInclusion Criteria• Age at ERT >6 - 36 months (1702) or <6 months (1602)Age at ERT >6 36 months (1702) or <6 months (1602)• Pompe Symptoms <12 months age• GAA in fibroblasts (4-MUG) <2%• Cardiomyopathy (+) pre-ERT (by echo)y p y ( ) p ( y )LVMI > mean+2 SD for age• Invasive ventilation allowed (1702 only)

rhGAA doserhGAA dose• 20 mg/kg/q2weeks or 40 mg/kg/q2weeks (1602)

21 bj t ll d i t d 1702 d 18 bj t i t d 1602• 21 subjects enrolled in study 1702 and 18 subjects in study 1602.

AGLU 1602 Study Design

Kishnani, P. S. et al. Neurology 2007;68:99-109

AGLU 1602:O ll S i l t 18 M th f A (1 ERT)Overall Survival at 18 Months of Age (1 yr ERT)

18/18 trial patientsp[100%]

1/62 untreated controls[2%; 95% CI: 0% - 6%]

Clinical Trial PatientsClinical Trial PatientsUntreated Historical Cohort 95% Confidence Intervals

Baseline EchocardiographyBaseline Echocardiography

Measure z-score

LV mass 8.5LV post wall 10.7Mass:vol 19.0EF (53%) - 1.7

E h di h P t lEchocardiography Protocol

• Data expressed as Z scores relative to BSA or age

• Core center for blinded interpretation of echo data

• Multiple readers

• Local training of echo staff for this specific protocol

LV MASS Z-Score Change with Myozyme

Kishnani, P. S. et al. Neurology 2007;68:99-109

Long-term outcome in 38 subjects in 1602/1702 M t di1602/1702 Myozyme studies

7 ventilator dependent 31 without ventilator support7 ventilator dependentat study start

31 without ventilator supportat study start

2 died 5 alive at study end on ventilator

17 NOT ventilator dependent

14 became ventilator dependent

1 died 16 alive and ventilatorfree at study endy

7 died

7 alive on a ventilator at study end

Group A: alive/free of assisted ventilation 16/38 (42%)

*one subject died prior to 2nd infusion; not included

Group B: death or assisted ventilation 22/38 (58%)10/38 deceased; 12/38 alive and ventilated

Baseline LV mass predicts clinical outcome group

Group A Group BBaseline Echo Measures

Alive and Vent Free (n=16)

Ventilation or Death (n=22) p

LVED 2 41 4 29 0 073LVED 2.41 4.29 0.073

EF z-score -1.59 -1.67 0.915

LVM z-score

5.08 7.71 <0.0001scoreMVR z-score

6.98 11.86 0.024score

LV mass and mass:vol ratio are lowerat 0 and 52 weeks in Group A

p=0.001 p=0.016p

Age at 1st infusion does not predict cardiac remodeling in cohort as a wholeremodeling in cohort as a whole

p=0.44 p=0.66

Summary of Cardiac Findings

• PR interval lengthens from baseline to near normal with ERT.LVM i i h d l i i h• LVM improves in the study population with some predictable minimal responders

• EF improvement may depend on favorable• EF improvement may depend on favorable wall stress.

• Survival data reflect overall improvement inSurvival data reflect overall improvement in cardiac function. Need to assess functional reserve and diastolic function.

Myozyme (for children <8 yrs and ex-USMyozyme (for children <8 yrs and ex-US

adults)Lumizyme (>8 yrs in US)

30

Increasing Capacity to Meet g p yNeeds Worldwide

BioreactorManufacturing

160 LFramingham, MA USA

2000 LAllston, MA USA

4000 LG l B l i

ManufacturingScale

Framingham, MA USA Allston, MA USA Geel, Belgium

Licensed in USand provides treatment

for Child U d i i f t

Previously licensed outside of US.

Intermediate scale is now b l t d i l

Licensed ex-US and provides treatment for all patients worldwide except

Children. Used in infant clinical studies.

obsolete and is no longer in production. Used in the

older children & adults clinical studies

(e.g. LOTS)

children in the US, including adults treated in ATAP.

Pending approval in the US and will be named

Lumizyme.Lumizyme.

Impact of Severe Hypertrophy on R i t F tiRespiratory Function

AGLU 1602:Overall Survival at 18 Months of Age (1 yr ERT)Overall Survival at 18 Months of Age (1 yr ERT)

18/18 trial patientsp[100%]

1/62 untreated controls[2%; 95% CI: 0% - 6%]

Clinical Trial PatientsClinical Trial PatientsUntreated Historical Cohort 95% Confidence Intervals

AGLU 1602:S i l F f ANY V til ti t 18 M thSurvival Free of ANY Ventilation at 18 Months

12/18 trial patients[67%; 95% CI: 45% - 88%][67%; 95% CI: 45% - 88%]

1/62 untreated controls[2%; 95% CI: 0% - 6%]

Clinical Trial PatientsUntreated Historical Cohort 95% Confidence Intervals

Late Onset Pompe Diseasep

Key to understanding results of current clinical studies

Late-Onset Pompe DiseaseKey Clinical Manifestations

• Progressive proximal muscle weakness,

Key Clinical Manifestations

especially in trunk and lower limbs• Gait abnormality

R i t t• Respiratory symptoms– Shortness of breath, fatigue on exertion,

obstructive sleep apnea

• Morning headache• Daytime somnolence

S li i• Scoliosis• Scapular winging• Low back pain• Low back painHirschhorn R, et al. In: The Metabolic and Molecular Bases of Inherited Disease. 2000:3389-3420.

Return to the Mouse Model of Pompe DiseaseDisease

P ti t d t t f th l tiPatient data prompts a further evaluation of respiratory deficiency

Diaphragm Involvement in Pompe (Gaa-/-)Diaphragm Involvement in Pompe (Gaa-/-)

PAS Staining of Glycogen

Gaa-/-

DiaphragmNormal

Diaphragmmonths

(Rucker, Development , 2004)

months

39

VentilationVentilation

Frequency (f): breaths per minuteq y ( ) p

Tidal Volume: Amt of air moved in/out of lungs with each breath (mL/breath)g ( )

Minute Ventilation: Freq * Tidal Volume (mL/min)

Peak Inspiratory/Expiratory Flow: Maximum inflow/outflow of air per sec ( L/ )(mL/sec)

Respiratory Assessment Respiratory Assessment Protocol

baseline hypercapnia

60 minnormal air

10 min6.4% CO2 / 94.6% O22 2

Tidal volume, Frequency, Minute Ventilation

Response to respiratory challenge is p p y gblunted in Gaa-/- mice

controlcontrolGaa-/-

MEAN±SEM

Muscle Specific Expression of hGAA in GAA -/- Mice

Spinal Cord Glycogen QuantificationSpinal Cord Glycogen Quantification

Neural deficits dominate respiratoryNeural deficits dominate respiratory dyfunction

Why Gene Therapy in Pompe?Why Gene Therapy in Pompe?

Si l d f t ith ll d fi d Single gene defect with well defined pathophysiology.

Ability to provide a single dose therapeutic with a systemic effect.

Endogenous source of gene product. Avoidance of circulating Ab / CTLg Differential fiber type processing

Gene transfer to motor neurons. Gene transfer to motor neurons.

Comparison of AAV9 at ~9.8 Å Resolution to AAV2 , AAV4 and AAV8.  Comparison of AAV9 at ~9.8 Å Resolution to AAV2 , AAV4 and AAV8.  

BA BA

AAV9 d l9 AAV9 modelAAV9 cryoC D EC

AAV2 AAV4 AAV8

GAA Vector Map:GAA Vector Map:GAA Vector Map:GAA Vector Map:rAAVrAAV11--hGAAhGAA

p43.2- hGAA

ITR

Poly A

Acid � Glucosidase ITRCMV

p

Systemic AAV delivery – Left ventricular massSystemic AAV delivery  Left ventricular mass

•All treatments significantly decrease LV mass at 3 months post‐treatment.All treatments significantly decrease LV mass at 3 months post treatment.

•No differences at one month were detected.Falk et al, unpublished

Phrenic Nerve Burst Amplitude is Improved postPhrenic Nerve Burst Amplitude is Improved post-injection with AAV-CMV-GAA (2.52 x 1010 particles)

rAAV2/1Untreated

rAAV2/1

0

0.05

rAAV2/1Untreated

∫Phrenic(v)

Untreated

0.2

-0.2

2 s

Phrenic(v)

0.1 s

Correction of Ventilation DeficitCorrection of Ventilation Deficit

Phase I/II: rAAVPhase I/II: rAAV11--hGAAhGAAPhase I/II: rAAVPhase I/II: rAAV11 hGAAhGAA

• Single site (UF)• Open label• Single dose in three injection sites• Dose escalation between groups• Intramuscular administration with direct vision by

thoracoscopythoracoscopy• N = 6 (2 cohorts of 3 subjects)

Cohort # 1 2Cohort # 1 2

Dose, vg 1x1012 5x1012

N 3 3

Time Line: Phase I/II rAAV1Time Line: Phase I/II rAAV1--hGAAhGAA

ERTV t

Da 14 0 3 14 30 45 60 75 90 180 365

Vector Injection

Day -14 0 3 14 30 45 60 75 90 180 365

Blood PCR

Immune response profile to AAV and hGAAp p

Respiratory function studies done up to 180d

General safety studies done throughout up to 365dGeneral safety studies done throughout up to 365d

Pompe Disease

Summary• Pompe disease is a continuum of clinical phenotypes,

ranging from rapidly progressive infantile-onset to more

Summary

g g p y p gslowly progressive, late-onset disease.

• All patients share a common pathophysiology: p p p y gydeficiency in GAA, leading to glycogen accumulation.

• Early diagnosis is the key to optimal patient y g y p pmanagement.

• Current management consists of multidisciplinaryCurrent management consists of multidisciplinarysupportive measures.

• Pivotal study of ERT completed and next generation• Pivotal study of ERT completed and next generation studies are underway.

AcknowledgementsAcknowledgements

University of FloridaLee Ann LawsonCathryn Mah

Genzyme Corporation1602-1702 PIs:Priya Kishnani Durham USCathryn Mah

David FullerDenise CloutierDarien Falk

Priya Kishnani, Durham, USMarc Nicolino, Lyon, FREd Wraith, Manchester, UKNancy Lesley Cincinnati USDarien Falk

Julie BerthyStacy PorvasnikKerry O. Cresawn NIH Collaborators

Ni R b d P l Pl t

Nancy Lesley, Cincinnati, USPaul Hwu, Taipei, TW

yChristina A. PacakThomas J. Fraites, Jr.Lara De Ruisseau

Nina Raben and Paul PlotzChildren’s Hospital BostonCarolyn Spencer

Brian CleaverNathalie Clement

Jami LevineSteve ColanCharlie Berul

Supported by NIH/NHLBI, NIDDK, NCRR, American Heart Association, Muscular Dystrophy Association, Genzyme and the University of Florida.